Project Summary/Abstract The goal of this study is to identify effective approaches and implementation strategies to empower young women at high risk for HIV in South Africa to utilize and persist on pre-exposure prophylaxis (PrEP) for HIV prevention during periods of elevated risk for HIV acquisition. PrEP uptake remains low among young women and use by FSW and AGYW halves by 1 month and continues a sharp decline during the first 3-6 months; effective strategies to target these critical periods are needed. The proposed study is embedded within TB HIV Care?s large-scale existing PrEP delivery program for young women across 12 sites in South Africa. The design leverages routinely collected data combined with strategic collection of de novo data and modifications to the delivery of existing implementation strategies to inform effective PrEP scale-up. Specific Aim 1: Measure ongoing PrEP implementation (e.g., acceptability, adoption, fidelity, cost) and identify implementation strategies associated with PrEP uptake and sustained use. Approach: Assess ongoing program implementation (e.g. direct observation methods, provider assessments, implementation logs) and conduct an interrupted time-series analysis using existing, program data (2016-2020) and changes to PrEP adherence interventions introduced over time (e.g. PrEP peer ambassadors, loyalty rewards program, etc.). These data will be used to identify effective PrEP interventions within the program and to further refine PrEP implementation strategies. Specific Aim 2: Evaluate the relative effectiveness of modified PrEP implementation strategies on increasing uptake and sustained PrEP adherence among marginalized young women. 2a. Approach: Use a cluster randomized design to evaluate the content and reach of PrEP social influence campaign, and its effect on PrEP uptake and persistence. 2b. Approach: Conduct a cluster randomized trial focused on modifying implementation strategies of existing peer support interventions to improve PrEP persistence, by varying the actor, intensity and duration of the implementation strategy. Relative effectiveness of implementation strategies at achieving 1, 4 and 7-month adherence will be compared and measured through programmatic PrEP refill data. Specific Aim 3: Identify a set of preferred PrEP implementation strategies for young women based on the projected population-level HIV prevention transmission modeling and cost-effectiveness analyses. Approach: We will extend, re-parameterize, and analyze our previously validated deterministic mathematical model of heterosexual HIV transmission in Southern Africa, which captures direct and indirect (spillover) prevention benefits of PrEP in the population of interest (AGYW and FSW) and the wider population. This will quantify the population benefits (infections inverted) of the PrEP implementation strategies and will include a full economic evaluation.